DESCRIPTION: How Plasmodium sporozoites invade hepatocytes, and develop within them, remains largely unknown. Our Preliminary Studies indicate that sporozoites can rapidly enter and leave host cells by disrupting the host cell plasma membrane. After few cycles of non-productive entry and exit, sporozoites invade host cells, and develop into the exo-erythrocytic stages. We propose that the passage of sporozoites through several cells is a required maturation step in the life cycle, and that it occurs during the parasite's journey from the site of entry in the skin to the liver. This hypothesis will be tested using cell and molecular biology approaches involving in vitro and in vivo models for hepatocyte infection. Our Preliminary Studies suggest that Plasmodium sporozoites ensure their complete development into the exo-erythrocytic stages by inhibiting apoptosis of hepatocytes. In contrast, irradiation of sporozoites prior to infection results in hepatocyte apoptosis. We propose to determine the genetic pathways involved in apoptosis inhibition of hepatocytes, and to identify the Plasmodium genes that contribute to this process, by examining gene expression in the host and pathogen in the presence and absence of irradiation. A protective immune response to malaria is induced by immunization with irradiated sporozoites. We propose that the apoptotic bodies derived from hepatocytes infected with irradiated sporozoites mediate the initiation of a protective anti-malaria immune response. Immunological and cell biological approaches will be used to further examine this hypothesis in vitro and in vivo.